Influence of Environmental Stimulation and Learning on Recovery After Injury

环境刺激和学习对伤后恢复的影响

• 批准号: 7502211
• 负责人: James William Grau
• 金额: $ 29.75万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502211
• 关键词: Accident and Emergency department; Acute; Address; Adverse effects; Affect; Arts; Axon; Behavioral; Behavioral Model; Biological Models; Bladder; Brain; Cell physiology; Cellular Assay; Chest; Clinic; Communication; Condition; Contusions; Development; Environment; Environmental Risk Factor; Equipment; Exhibits; Exposure to; Felis catus; Fiber; Foundations; Goals; Grant; Growth; Hour; Human; Incidence; Inflammation; Injury; Intractable Pain; Ischemia; Kidney Failure; Laboratories; Learning; Leg; Long-Term Effects; Lumbar Regions; Maps; Mediating; Modeling; Motor; Myelin Sheath; N-Methyl-D-Aspartate Receptors; Neurons; Neurophysiology - biologic function; Nociception; Numbness; Oligodendroglia; Operant Conditioning; Operative Surgical Procedures; Outcome; Pain; Pain management; Paralysed; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Physiological; Positioning Attribute; Procedures; Process; Rattus; Recovery; Regulation; Relative (related person); Research; Research Personnel; Rodent; Role; Sacral spinal cord structure; Sensory; Severities; Shock; Signal Transduction; Site; Spinal Cord; Spinal Injuries; Spinal cord injury; Stimulus; Stress; Structure; Substance P; Substance P Receptor; Supporting Cell; Synapses; System; Testing; Time; Tissues; Translating; Treatment Effectiveness; Walking; Week; Work; central sensitization; clinically significant; day; improved; injured; innovation; mortality; nerve injury; neurobiological mechanism; outcome forecast; painful neuropathy; prevent; programs; protective effect; research study; response; therapy design; transmission process; white matter

DESCRIPTION (provided by applicant): Prior research has shown that neurons within the spinal cord are sensitive to response-outcome (instrumental) relations. Learning in the isolated spinal cord has been studied by cutting communication with the brain using a thoracic transection. Transected rats given shock to one hind leg whenever the leg is extended learn to maintain the leg in a flexed position, thereby minimizing net shock exposure. Rats given shock independent of leg position (uncontrollable shock) do not learn and exhibit a learning deficit when later tested with controllable shock. Evidence suggests that uncontrollable stimulation impairs learning because it induces a form of central sensitization that saturates NMDA receptor mediated plasticity. Uncontrollable stimulation also impairs recovery after a contusion injury. Just 6 min of stimulation 24 hrs after injury leads to poor sensory/motor recovery and this effect is evident 6 weeks later. Uncontrollable stimulation also increases the incidence of renal failure and signs of neuropathic pain. Our working hypothesis is that unregulated nociceptive transmission (pain signals) engages cellular mechanisms that impair recovery after spinal injury. Our long-term objectives are to identify: the circumstances that cause this effect, the neurobiological mechanisms involved, and procedures that can be used to block the adverse effect of uncontrollable nociceptive stimulation. Three aims are proposed that will detail the stimulus conditions that impact recovery, the relative role of brain systems, and the relation to central sensitization. The experiments build on a decade of research detailing the conditions, and neurobiological mechanisms, that impact function in the isolated spinal cord. Aim 1 examines the stimulus conditions that affect recovery. It is recognized that a moderate contusion spares some sensory fibers that allow pain transmission to supraspinal structures. It is not known whether, and how, brain systems contribute to the long-term effects of stimulation on recovery. If brain systems are involved, less intense, and more widely spaced, stimulation should impact recovery. Aim 2 will clarify the role of brain systems using physiological and pharmacological manipulations that impact spared fibers. We also examine whether stimulation affects recovery in the absence of input at, or below, the site of injury. Aim 3 will evaluate whether the induction of central sensitization (through peripheral inflammation) impairs recovery and whether pharmacological manipulations that prevent central sensitization have a protective effect. The loss of tissue after neural injury reflects the net effect of both the acute injury and secondary processes that extend from hours to days after injury. By identifying factors that influence these secondary processes, treatments can be developed to reduce their harmful effects. Treatments now used to control pain in other situations (e.g., an epidural) could benefit recovery. The present grant will evaluate this possibility.

描述（由申请人提供）：先前的研究表明，脊髓内的神经元对反应结果（工具）关系敏感。通过使用胸腔横断来切割与大脑的通信，已经研究了孤立的脊髓中的学习。每当腿扩展时，横向大鼠会使一条后腿受到冲击，以将腿保持在弯曲的位置，从而最大程度地减少净冲击曝光。在腿部位置独立于腿部的大鼠（不可控制的冲击）时，当以后用可控的冲击测试时，不会学习和表现出学习缺陷。有证据表明，无法控制的刺激会损害学习，因为它诱导了一种饱和NMDA受体介导的可塑性的中心敏化形式。无法控制的刺激还会损害挫伤损伤后的恢复。受伤后24小时仅6分钟的刺激导致感觉/运动恢复差，并且这种效应在6周后显而易见。无法控制的刺激还增加了肾衰竭的发生率和神经性疼痛的迹象。我们的工作假设是，不受管制的伤害感受传播（疼痛信号）会涉及细胞机制，这些机制会损害脊柱损伤后的恢复。我们的长期目标是确定：引起这种影响的情况，涉及的神经生物学机制以及可用于阻止无法控制的伤害感受刺激的不良影响的程序。提出了三个目的，该目标将详细说明影响恢复的刺激条件，大脑系统的相对作用以及与中央敏化的关系。实验基于十年的研究，详细介绍了在孤立的脊髓中影响功能的疾病和神经生物学机制。 AIM 1检查影响恢复的刺激条件。人们认识到，中等挫伤可以避免一些感觉纤维，从而使疼痛传播到上脊髓结构。尚不清楚大脑系统是否以及如何有助于刺激对恢复的长期影响。如果涉及大脑系统，较小的强度且间距更广泛，则刺激应影响恢复。 AIM 2将使用影响较低纤维的生理和药理操作来阐明大脑系统的作用。我们还检查刺激是否会在没有输入的情况下或以下影响损伤部位。 AIM 3将评估中央敏感性（通过外周炎症）的诱导是否会损害恢复以及防止中央敏化的药理操作是否具有保护作用。神经损伤后组织的损失反映了急性损伤的净作用和从损伤后数小时延伸到几天的次要过程的净效应。通过识别影响这些次要过程的因素，可以开发治疗以减少其有害影响。现在用于控制其他情况下疼痛的治疗方法（例如硬膜外）可能会受益。目前的赠款将评估这种可能性。